Hydrocarbon Stapled Peptides as Modulators of Biological Function

Abstract

Peptide-based drug discovery has experienced a significant upturn within the past decade since the introduction of chemical modifications and unnatural amino acids has allowed for overcoming some of the drawbacks associated with peptide therapeutics. Strengthened by such features, modified peptides become capable of occupying a niche that emerges between the two major classes of today's therapeutics-small molecules (<500 Da) and biologics (>5000 Da). Stabilized α-helices have proven particularly successful at impairing disease-relevant PPIs previously considered "undruggable." Among those, hydrocarbon stapled α-helical peptides have emerged as a novel class of potential peptide therapeutics. This review provides a comprehensive overview of the development and applications of hydrocarbon stapled peptides discussing the benefits and limitations of this technique.

Stapled peptide design: principles and roles of computation

“…Since then, a range of studies has demonstrated the potential utility of hydrocarbon stapled peptides in the treatment of various human diseases. Two hydrocarbon stapled peptides have reached clinical trials, epitomising the remarkable progress made in this field within the past 15 years [49]. A paradigm for stapled peptide design is also gradually being developed based on the huge body of experimental data that has been collected so far.…”

“…They have also shown potential as therapeutic agents for various other diseases, such as HIV [44,45], diabetes [46], cardiovascular disease [47], and respiratory infection [48]. Two hydrocarbon-stapled peptides developed by Aileron Therapeutics are currently undergoing clinical trials for the treatment of orphan endocrine disorders and malignant tumours [49].…”

Direct Modulation of Small GTPase Activity and Function

“…[80,81] Stabilized a-helices have proven highly successful in inhibiting protein-protein interactions (PPIs), with hydrogen-bond surrogates (HBS) and stapled peptides resembling the most advanced approaches within that field. [83,84] HBS3 (10)isaderivative of aHwith enhanced solubility and was designed as an inhibitor of the Ras-SOS interaction ( Figure 6b). It shows moderate affinity for GDPbound (K d = 158 mm)a sw ell as nucleotide-free (nf) H-Ras (K d = 28 mm).…”

“…[136] Peptide stapling [84] can be used to stabilize the a-helical conformation of ag iven peptide by introduction of an all-hydrocarbon macrocyclic bridge to interconnect two turns of ah elix. In af irst step,c omplexes of Rab proteins with various interaction partners were analyzed with respect to their interaction surface to identify suitable a-helical binding domains.T he top-rated peptide fragments were tested with arepresentative set of six different Rab proteins in all nucleotide binding states to yield four peptides which bind nucleotide-free Rab proteins in the low micromolar range.I ncorporation of hydrocarbon staples into these peptide sequences produced alibrary of stapled peptides which bind arepresentative set of Rab proteins in the nucleotide-free form with varying selectivity and affinity down to the submicromolar range.…”

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“…Peptidomimetics have found numerous applications in the fields of drug designing, drug delivery, synthetic hormones, growth factors and many other such aspects of health care where physiology encounters its limits [19][20] .…”